GABA is the most abundant inhibitory neurotransmitter in the mammalian brain. GABA controls brain excitability by exerting inhibitory functions on neuronal membranes by altering their permeability to specific ions. Binding of GABA to the GABAA-type (GABAA) receptor increases the permeability of neuronal membranes to chloride ions (Cl−). In most neurons the relative Cl− ion concentration is greater outside than inside the membrane. Thus, selective permeability to Cl− initiated by GABA binding forces Cl− into the cell. The majority of fast inhibitory synaptic transmission is a result of GABA binding to the GABAA receptors. GABAA receptors are ubiquitously expressed throughout the CNS with almost all neurons staining for their presence. The GABAA receptor is a hetero-pentameric protein structure of the nicotinic acetylcholine receptor superfamily. Native GABAA receptors are formed from at least 19 related subunits. The subunits are grouped into α, β, δ, ε, π, and ρ families. The most prevalent combination of GABAA receptors is a stoichiometric combination of the 2×α, 2×β, and 1×γ subunits, with the remaining subunits relegated to substituting for the y subunit during specific development expression or in highly specific brain region localization. The adult brain predominately expresses the α1β2γ2 subunit combination (60%) with the α2β3γ2 and α3βnγ2 subunits comprising the majority (35%) of the remaining receptors. The relative effects of GABA are influenced by the receptor subunit expressed in a specific brain region or neuronal circuit.
The neurophysiological effects of GABA result from a conformational change that occurs when GABA binds to the GABAA receptor. The GABAA receptor and the associated ion channel complex (GRC) recognize many compounds that allosterically enhance the ability of GABA to bind to the GABAA receptor. The allosteric modulators have distinct sites on the GRC. These sites are separate and unique from the site that recognizes GABA. The most widely studied and characterized class of allosteric modulator of the GRC are those that interact with the benzodiazepine(BZ)-site.
Alternative sites for modulating the GRC have been described. For example, neuroactive steroids are non-hormonal steroids that bind and functionally modulate the GRC. The current role of neuroactive steroids in GABAA receptor pharmacology is supported by overwhelming evidence. Electrophysiological and biochemical techniques have confirmed the capacity of neuroactive steroids to allosterically modulate the GRC through a unique site of action. Experimentally, neuroactive steroids exhibit a pharmacological profile similar, but not identical, to the benzodiazepines. Neuroactive steroids have anxiolytic, anticonvulsant, and sedative-hypnotic properties.
It is well-documented that the GRC is responsible for the mediation of anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA or facilitate the effects of GABA (e.g., the therapeutically useful barbiturates and benzodiazepines (BZs) such as Valium) produce their therapeutically useful effects by interacting with specific modulatory sites on the GRC receptor complex.